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Keywords:

  • contracture;
  • keloid;
  • X-linked;
  • new syndrome;
  • uric acid kidney stones

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

We report on a family with an apparently undescribed syndrome involving joint contractures, keloids, an increased optic cup-to-disc ratio, and renal stones. The propositus presented at 9 years of age with congenital contractures of his distal interphalangeal (DIP) joints, progressive stiffness of the shoulders and neck, a large optic cup-to-disc ratio, and mildly dysmorphic facies. He otherwise has been normal. The propositus's brother, uncle, great-uncle, a half great-uncle, and six male half-cousins once removed also have DIP joint stiffness. The propositus' mother and brother also have an increased optic cup-to-disc ratio. In addition, the great-grandfather, the uncle, the same six male half-cousins once removed, and an affected daughter of a half-cousin have keloids with the earliest age of onset of the keloids being 12 years. Further, three of the above affected males have had uric acid renal stones. Dupuytren contractures and subcutaneous nodules were also present in some affected males. Given the family history, the pattern of inheritance appears to be X-linked. An extensive literature search failed to reveal any previous reports associating these manifestations and this inheritance pattern. Therefore, we think the condition in this family comprises a new genetic syndrome. © 2008 Wiley-Liss, Inc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Postnatal joint contractures have multiple causes including contractions or adhesions of the tendons, contractures of the ligaments or joint capsules, thickening of the soft tissue, thickened or inadequate skin cover or scarring, and bone exostoses within the joints [Curtis, 1989]. Risk factors for Dupuytren contracture include northern European ancestry, age, trauma, alcoholism, diabetes mellitus, epilepsy, and a positive family history [Ling, 1963; Wilbrand et al., 1999; Bayat and McGrouther, 2006]. By contrast, keloids are seen predominantly among individuals of African American descent [Gonzalez-Martinez et al., 1995; Marneros et al., 2001]. Although keloids and Dupuytren contractures both are fibroproliferative disorders, they rarely are seen coexisting in the same patient, with the exception being a rare condition called polyfibromatosis, which includes various cutaneuous fibrotic manifestations [Fenton et al., 1986; Gonzalez-Martinez et al., 1995; Tredget et al., 1997]. The cause of polyfibromatosis is currently unknown. An increased optic cup-to-disc ratio (normal population mean = 0.43; SD = 0.14 [Crowston et al., 2004]) is also uncommon, especially among children, and viewed as suspicious for glaucoma [Erkkila and Laatikainen, 1979; Good and Quinn, 1984; Ramrattan et al., 1999; Mansberger et al., 2003]. The optic disc, located where the optic nerve exits the posterior of the eye, contains a central depression or the cup. Progressive increase in the optic cup diameter, and thus the optic cup-to-disc ratio, may be indicative of deterioration of optic nerve fibers. Uric acid renal stones arise because of abnormally low urine pH, and are common in patients with gout, diabetes mellitus, and the metabolic syndrome, the latter of which is comprised of a collection of risk factors for cardiovascular disease including hypertension, hyperglycemia, hyperlipidemia, and obesity [Coe et al., 2005]. Of all patients with renal stones, nine percent have uric acid stones [Coe et al., 2005].

Here, we report on a family that displays distal interphalangeal (DIP) joint limitations, Dupuytren contractures, keloid formation, increased optic cup-to-disc ratio, and uric acid renal stones in an apparently X-linked pattern of inheritance. To our knowledge, this is the first family reported with co-segregation of these characteristics, and we think this family represents a new genetic syndrome.

CLINICAL REPORTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

The pedigree of the family is shown in Figure 1. There is no known consanguinity. The clinical features of nine affected family members are presented below and summarized in Table I.

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Figure 1. The pedigree of the family.

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Table I. Features of Affected Individuals
Affected individualaExaminedBy report
III-3IV-3IV-12V-1V-2III-2IV-2V-10I-1III-10IV-8IV-10IV-11IV-13IV-14IV-18
  • −, feature absent; +, feature present; U, presence or absence of feature unknown; UA, uric acid.

  • a

    See Figure 1 to view pedigree.

Contractures/joint limitation
 Neck/shoulders+++UUU+U++U
 Elbows++UUUUUUUU
 Hands++++++++++++U
 Knees+++UUUUUUUU
 Ankles++UUUUUUUU
 ToesU+++U+U+U+U
Cutaneous/subcutaneous
 Keloids/hypertrophic scar++/−+++UU++++
 Subcutaneous nodules++++UUU+UU+
Other findings
 Increased optic cup-to-disc ratioU+U++++UUUUUUUUU
 UA renal stones+++U
 Chest asymmetry+U++UUUUUUUUUUU

Individual V-1

The proband (V-1, Fig. 1) is a 12-year-old Caucasian male who presented with a history of congenital contractures of the DIP joints and progressive stiffness of his shoulders and neck. The prenatal history was uneventful. His growth and development have been normal. At age 12 years, his height was at the 90th centile (157.4 cm), weight at the 50th centile (40.1 kg), and occipitofrontal circumference (OFC) at +0.5 SD (54 cm). He receives some tutoring in school, but does not have any recognized learning disabilities. At the age of 9 years he had a mildly dysmorphic facies that included deeply set eyes, slightly downslanting palpebral fissures, slight prominence of the alae nasi and upper philtrum and micrognathia. He also had mild chest asymmetry with the right side larger than the left. On the left hand, he had radial deviation of the 5th finger, contractures of the 4th and 5th fingers, and hypoplastic distal flexion creases on fingers 2–5 (Fig. 2A). On the right hand there was radial deviation and camptodactyly of fingers 3–5 (Fig. 2A), a hypoplastic distal flexion crease on the 3rd finger, and absent distal flexion creases on the 4th and 5th fingers. His proximal interphalangeal (PIP) and metacarpophalangeal joints were normal bilaterally. The middle portions of the 3rd–5th fingers and nails were broad. He also had mild limitation of full extension and reduced supination of the elbows, decreased flexion of the hips, and mild limitation of the knees and ankles. The 5th toes were short. A scar from a recent cut on his left wrist was hypertrophic, but prior scar development was normal. Neurologic evaluation was normal, including strength. He also had large optic nerves and an increased optic cup-to-disc-ratio (0.8 bilaterally), but on ophthalmologic examination his eyes were otherwise normal with no evidence of glaucoma. Radiographically, there was thinning and widening of the outer and inner tables of the skull, mild concavity of the thoracic vertebrae, mild angulation of the 5th digits, narrow pelvis, elongation of the 2nd and 3rd toes bilaterally, squaring of the distal phalanges of the toes, and lack of tapering to the metacarpals and metatarsals. The phalanges were not widened. Bone age in the hand was increased (chronologic age 9equation image years, phalangeal age 12equation image years, and carpal bones 14 years). Chromosomal karyotype (at the 664 band level) was normal. Also comparative genomic hybridization evaluation (Signature Genomics Laboratories, LLC. SignatureChip version 4.0) was normal.

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Figure 2. Contractures of the two affected males. A: Proband (V-1, Fig. 1), age 12. Note more severe contractures of the fifth fingers and soft-tissue widening of the middle portions of the fingers 3–5. B: Left hand of individual III-3 (Fig. 1) at age 51 years. Note ulnar deviation of the 2nd digit, the severe contracture of the 3rd digit and the less severe contractures of the 4th and 5th digits. C: Left hand of individual III-3 (Fig. 1) at age 51 years. The 4th and 5th fingers have been removed surgically because of severe contractures. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

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Individual V-2

Individual V-2 (Fig. 1) is the 7-year-old male full sibling of the proband. His growth and development also have been normal. On exam at age 7, his facial appearance was normal except for slightly prominent ears. He had mild chest asymmetry and a right supernumerary nipple. He developed contractures of his joints around age 5, which included limitation of his finger DIP joints bilaterally. There were broad digits with hypoplastic distal flexion creases on the 4th and 5th fingers of his right hand, and an almost absent distal flexion crease on the 4th finger of his left hand. Flexion was limited to 45° in all DIP joints, except the left 4th finger where there was only 20°of flexion. He had marked limitation of glenohumeral and scapulothoracic movement of his shoulders and flexion and extension of his knees, and mild limitation of movement of the ankles. His 5th toes were short. He also had a freely movable subcutaneous nodule at the back of his neck. No scars were present. He also had an increased optic-cup-to-disc ratio (0.6 bilaterally). We have not determined his bone age.

Individual IV-3

Individual IV-3 (Fig. 1) is the 30-year-old maternal uncle of the proband who had onset of keloid development at age 12, and was diagnosed to have uric acid renal stones at age 20. On physical exam he has slight frontal bossing, mild bitemporal narrowing, a prominent temporomandibular joint, mild chest asymmetry, and mild pectus excavatum. On the right hand, he had slight limitation to flexion of the thumb's interphalangeal joint, and decreased movement of his DIP joints on the 2nd and 3rd fingers with hypoplastic creases over these joints. The 4th finger had an absent distal flexion crease and flexion was limited to approximately 10° at the DIP joint. The limitation of flexion of this joint has progressed from 20° of movement when we first examined him 2 years prior. On his left hand, the 3rd and 4th DIP joints were limited to 5° and 10° of movement, respectively, and the 4th distal flexion crease was absent. The 5th finger DIP joints and all PIP joints were normal. He had mildly reduced supination on the right, but normal range of motion in his wrists and elbows. There were restricted movement of his left toes and a subcutaneous knot on the arch of his foot. All of his toes were slightly short. He also had striae on his hips and a number of keloid scars, including an area of a skin graft on his right inner thigh and multiple acneform lesions on his shoulders (Fig. 3A,B). He also has an increased optic cup-to-disc ratio (0.6 bilaterally). His serum uric acid level was 4.4 mg/dl (normal range = 3.6–8.3 mg/dl).

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Figure 3. Keloid formation. A: Extensive keloid formation on right inner thigh at a site of skin graft following a burn in individual IV-3 (Fig. 1), and (B) keloid formation and acneform lesions in the same individual. C: Keloid formation at appendectomy site in individual V-10 (Fig. 1), a female who is otherwise normal. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

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Individual III-3

Individual III-3 (Fig. 1) is the 51-year-old maternal great-uncle of the proband. He is reported to be the most severely affected relative. He reported onset of his contractures at age 16. His contractures became severe around the age of 35 and reportedly have been exacerbated by excessive alcohol use. When we examined him at age 51, he was normocephalic (OFC = 58 cm, 97th centile) and had an increased chest diameter. His hands had severe contractures of the fingers and palms bilaterally (Fig. 2B,C). On the right hand, the 4th and 5th fingers have been surgically removed because of the severe contractures. There was no or limited movement of the remaining DIP joints with no movement in the 2nd digit and 10° of movement in the 3rd. The 2nd and 3rd PIP joints were also limited with 20° and 40° of flexion, respectively. These joints also have calluses over the knuckles. All the right metacarpophalangeal joints were limited to 30° of movement. On the left hand, there was limitation of the DIP joints with 45°, 0°, 20°, and 45° of flexion for the 2nd, 3rd, 4th, and 5th digits, respectively. Flexion of the 2nd, 3rd, and 4th PIP joints was also limited with 60°, 20°, and 60° of movement, respectively, and the metacarpophalangeal joints were limited to 30°, 5°, 20°, and 45° of movement for the 2nd, 3rd, 4th, and 5th digits, respectively. He also had limited supination bilaterally, and mild limitation of full extension at the elbows and knees. His neurologic exam was normal. Normal scarring was noted with no keloid formation. He also had multiple varocositities of the lower extremities.

Individual IV-12

Individual IV-12 (Fig. 1) is the 46-year-old maternal half-cousin once removed of the proband who has a history of uric acid renal stones and joint stiffness. When evaluated at age 44, he complained of pain in his shoulders, hands, lower back, knees, and feet. He had stiffness of his fingers at the DIP joints bilaterally and limited rotation of his neck. He also had mild hypertrophic scarring over the sternum where he had repair of an atrial septum defect and tricuspid valve stenosis at age 35. Multiple lipomas were present on his neck, chest, abdomen, and back.

Female Family Members

Multiple maternal female family members showed mild features similar to the affected males. For instance, the proband's mother (IV-2, Fig. 1) has large optic nerves, although not as large as observed in the proband and an increased optic cup-to-disc ratio (right = 0.6; left = 0.55). She had no other findings of the family's condition. Individual V-10 (Fig. 1) is the 18-year-old half-second cousin to the propositus and daughter of Individual IV-12 (Fig. 1). She had a keloid scar on the abdomen from an appendectomy (Fig. 3C). The 52-year-old maternal grandmother of the proband (III-2, Fig. 1) reported arthritis and had significant shortening of the 4th and 5th toe on the left. The most severely affected female family member is a maternal female half-cousin once removed (IV-11, Fig. 1) who is reported to have hand contractures and keloids. She has not been examined in person to determine the severity of these findings, however. Although we have no information on Individuals II-11, III-4, III-5, III-6, and III-8, we concluded that they are obligate carriers because each has one or more affected sons.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

We describe a family with a constellation of features that to our knowledge has not been reported previously. The salient features include joint contractures, keloid formation, large optic cup-to-disc ratio, and uric acid renal stones. In an apparent X-linked pattern of inheritance, multiple maternal male family members exhibit these features with finger contractures developing at various ages but having been present at birth in some cases, and keloid formation occurring as early as 12 years. Additionally, several maternal female family members exhibit milder findings, including the proband's mother who possesses an increased optic cup-to-disc ratio without any other findings of the syndrome. Features are variable among all affected family members.

These findings have some similarities with a group of connective tissue disorders called fibromatoses, which are highly variable and characterized by fibroblast proliferation and slow progression [Young and Fortt, 1981; Fenton et al., 1986]. However, an extensive literature review did not reveal any other reported families with the exact constellation of findings seen in the family cited here. There are several reports that have noted the association of skin fibromas, keloids, knuckle pads, Dupuytren contractures, and other findings in the condition, hereditary polyfibromatosis [Touraine and Ruel, 1945; Marshall, 1970; Young and Fortt, 1981]. Touraine and Ruel's 1945 study supported an autosomal dominant pattern of inheritance with variable expressivity in hereditary polyfibromatosis. A case report by Fenton et al. 1986 cited an adult male with polyfibromatosis characterized by bilateral Dupuytren contractures and numerous keloid nodules. However, these authors reported no other affected family members, nor was the patient reported to have limited range of motion in his DIP or other joints as experienced by affected males in our family. Additionally, the disease course in Fenton et al.'s 1986 patient was more aggressive than that seen in our family. Other reports have described the concurrence of Dupuytren contractures and keloids with family history supportive of autosomal dominant inheritance [Ling, 1963; Gonzalez-Martinez et al., 1995]. The occurrence of congenital progressive digital contractures was described by Foucher et al. 2001, but the families they reported did not have the other findings seen in our family. Furthermore, while our family does not meet the full definition for distal arthrogryposis syndrome [Hall et al., 1982a,b; Bamshad et al., 1996] as the contractions in most of the affected males developed following birth, one could make the argument that this is distal arthrogryposis since at least some affected individuals have abnormal flexion creases of the fingers. The latter observation suggests that there was limited joint movement in utero even though contractures were not present at birth.

Although the family reported here shares some components in common with polyfibromatosis including keloids and Dupuytren contractures, there are also several differences including the occurrence of renal stones and increased optic cup-to-disc ratio. Since diagnostic testing for polyfibromatosis is not available, we cannot rule out that our family does not have polyfibromatosis. However, we believe that it is unlikely that the features in our family not associated with polyfibromatosis, that is, increased optic cup-to-disc ratio and uric acid renal stones, are co-segregating with contractures as a separate genetic condition.

While we know of no gene on the X chromosome that would account for the defects found in this family, it is possible that the disparate findings in the syndrome described here result from a contiguous gene deletion on the X chromosome. However, no deletion was detected on array comparative genomic hybridization (Signature Genomics Laboratories, LLC. SignatureChip version 4.0) of the proband. Additionally, we are not aware of an animal model with similar features.

Based on the family's history, the most likely pattern of inheritance appears to be X-linked as all the affected males are related through unaffected or minimally affected females, there are no reported fully affected females, and there is no evidence of male-to-male transmission. In addition, the presence of an increased optic cup-to-disc ratio in the mother and a female relative with keloid formation is consistent with partial expression in female carriers. Autosomal dominant with sex-influenced expression is also possible in this family, but we think this latter mode of inheritance is much less likely. The unique findings in this family appear to comprise a newly recognized syndrome.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

We thank Dr. Gary Bellus and Dr. Mervin Cohen for their assistance with evaluation of this family. We also wish to express our great appreciation to the family who has been most involved in this project.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CLINICAL REPORTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES